Are there sex differences in corpus callosum pathology ?
Neurons are brain cells whose most characteristic property is to rapidly
transmit information over certain distances, which in the spinal cord, can
reach as far as a meter. The part of the
neuron that carries the information over any distance is called the axon. The axonal part of the neuron is often called
the neuron fiber. One of the major
fiber systems in the human brain is the main commissure connecting the two
hemispheres called the corpus callosum.
Estimates of the number of neurons contained in the human corpus
callosum range from 200 to 800 million.
A careful electron microscopy study for the purpose of a neuron count in
the corpus callosum has yet to be carried out in humans. The corpus callosum, like other neuronal systems of the
brain, starts developing late in
prenatal development, during the third
trimester of pregnancy, and undergoes
exuberant overdevelopment followed by massive and rapid pruning. In short,
it contains many more neurons at one (prenatal) stage of its development
than at its (post-natal) maturity, many
of its neurons being required to retract and die. This is a normal process of prenatal
development called neuronal mortality.
The corpus callosum is easy to measure macroscopically (with a simple
ruler) in a brain sliced down the middle from front to back, for it measures about six centimeters in
length and is about a centimeter large.
Many studies have been carried out to determine whether the corpus
callosum of the human is sex-dimorphic,
both using brains of dead people, as well as using radiological images
of living patients. My reading of that
extensive literature has led me to conclude that, in the human adult, if there exists any macroscopic sex
difference in the corpus callosum, it is
only in relation to handedness -left
handed men having the largest callosi and right handed women having the
smallest. So I don't want to make a
case for a basic sex difference here.
However, perhaps because its prenatal development is subject to very
rapid changes during a brief period, the
corpus callosum is very sensitive to teratogens (substances which cause
deformities in fetuses). For
example, as has been extensively studied
in rats (less so in humans) maternal consumption of alcohol during the second
or third trimester can cause agenesis (failure to grow) of the corpus
callosum, and this affects male (pups)
more than females. The same effect is
observed with prenatal exposure to cocaine.
This sex difference is rather well established in the animal literature,
having now been consistently replicated. Furthermore, in rat fetuses, contrarily to humans, there is a basic sex difference in callosal
dimension. Males have larger callosi.
Electron microscopes have now been extensively used to investigate callosal neurons
in rats. Axon number calculations
revealed no sex differences in total axon number. Males, however, have
significantly more myelinated axons than females. Hormonal masculinization of female rat
fetuses results in development of a larger corpus callosum. Even more interestingly, hormonal feminization of male rat fetuses
results in development of a smaller corpus callosum !
Could it be then,
I wonder, that steroid hormones
influence the development of the microstructure of the human corpus callosum
? Or is there anything special about
the human corpus callosum as a function of sex -in a manner we have not yet
detected ? If the male sex is more
subject to teratogenic callosal aberration,
would the effect occur with any brain stressor during the late fetal
period ? Would this be particularly
typical of male-prevalent disorders ? Male-prevalent disorders include fetal
alcohol syndrome, fetal malnutrition syndrome,
and several hereditary disorders known to affect fetal brain development
in a diffusely unfavorable manner such as dyslexia, hyperactivity, Tourette's disease, and schizophrenia. There is preliminary evidence to the effect
that the corpus callosum does not function normally and/or looks abnormal in
hyperactivity, dyslexia, schizophrenia, Gilles de la Tourette disease, human fetal alcohol syndrome, and developmental delay due to maternal
malnutrition. I do not believe that the
callosal abnormalities are the sole cause, or even the most important cause of
any of the above mentioned syndromes.
I do believe however that the corpus callosum deserves study in the
context of the developmental neuropsychology of sex differences in each of
these specific disorders.
One example which will help highlight this call for
research is alexithymia.
Alexithymia, as its etymology
indicates, consists of an inability to "read" one's emotions. More specifically in fact, it consists of a relative inability to give a
verbal account of the emotions one is going through at a given time. If neuropsychology is anything at all, it
is the study of hemispheric specialization.
The main specializations of the human hemispheres are verbal
specialization of the left hemisphere and emotional and visuospatial specialization
of the right hemisphere. Alexithymia is
therefore an extremely interesting condition for neuropsychologists to
investigate because while leaving intact one important specialization of each
hemisphere (verbalization for the left,
and emotion for the right), it
represents a failure of integration of the two. This directly leads to the hypothesis that
the corpus callosum could, and perhaps
should, be the site of dysfunction in alexithymia. Indeed,
several investigations have recently shown that this is the case. When a patient has an epileptic focus in one
hemisphere, an electrical barrage
occasionally is triggered from that focus,
jumping across the hemispheres in a cascade leading to a grand mal attack (generalized convulsions). When the epilepsy resists most anticonvulsant
drugs, neurosurgeons sometimes cut the
corpus callosum (the operation is called a callosotomy) in the hope of
constraining the electrical disturbance to the one hemisphere -containing the
epileptic focus. This approach has
often been successful in completely preventing grand mal attacks. Several investigations have now shown that
such patients, though capable of normal
(or very close to normal) emotion and verbal abilities, have a disproportionate difficulty in
expressing, verbally, the emotions they are undergoing in
emotiogenic (emotionally upheaving) situations. What does all of this have to do with sex
differences, you may ask ? You already
know the answer of course. Normal boys
and men score higher (i.e., are worse) on tests of alexithymia than do normal
girls and women. This finding has been
replicated by separate research teams using several different tests of
alexithymia, in different cohorts of normal
people.
A
vignette on a case of alexithymia and callosal agenesis
In 1980, Buchanan, Waterhouse and West published a report of Mr
H, an alexithymic with callosal agenesis
(absence of development of the corpus callosum before birth). This case is particularly revealing because
he had no brain abnormalities which are commonly associated with callosal
agenesis and he was quite healthy and had a normal IQ. He was seen at age 37. He was slightly uncoordinated, had a reading disability, and complained of emotional distress and
inadequacy. During one meeting with the
authors of the report, he described the
funeral of his only sister in great detail.
During this account, he wept
copiously. Upon being asked whether
remembering the incident was still painful for him he “ looked up
quizzically, smiled and then laughingly responded: I don’t know,
I just can’t explain what I feel. ” Insistent probing was ineffective in
obtaining any emotional label for what he had felt during the account. As the authors of the report explain, this condition, alexithymia,
gives an impression of emotional immaturity and lack of
introspection. Mr H has little explicit emotionally-laden inner
life, is drab, and even bores
himself. He has always been very
dependent on the significant women in his life (mother, wife).
What little relevant information we have from research
on hyperactivity, dyslexia, schizophrenia, Gilles de la Tourette disease, human fetal alcohol syndrome, and developmental delay due to maternal
malnutrition, points in the same
direction. These predominantly male
disorders seem to be associated with callosal dysfunction and/or
abnormality. Dyslexia is a
particularly interesting case in point:
interhemispheric relay and the corpus callosum have been studied in more
detail in this disorder. It makes sense
to think of an interhemispheric relay problem in this disorder. First,
several investigations have found that the corpus callosum is larger in
dyslexics than in normals. Second, physiological and behavioral investigations
have found that interhemispheric relay is faster in dyslexics than
normals. Although I don't wish to get
into the technical details of how this is achieved, I do wish to provide an interpretation of how
the callosal dysfunction could contribute to the reading problem of dyslexics. It seems plausible, though not yet fully
proven, that one of the problems of
dyslexics could be that the processing of the written word, which in normal children is accomplished to a
very large extent by the left hemisphere,
is disrupted in dyslexics by concomitant processing occurring in the
right hemisphere. Since post-mortem
histology has shown that most developmental dyslexics have cortical ectopias
(local abnormalities in tissue composition) in the posterior temporal lobe,
more than elsewhere, it would be reasonable to suspect that it is the mid
posterior part of the corpus callosum that is the most disturbed in its
function.
Tourette's disease is another very interesting case
supporting speculation about a callosal disturbance which could relate to some
of the behavioral abnormalities afflicting these patients. One of the most extraordinary symptoms in
psychiatry has got to be the Tourettian coprolalia (filthy language). Gilles de la Tourette, a French physician, was the first to note that there is a
recurrence of cases in families, with
multiple changing complex tics, including gestures and vocalizations. What is extraordinary about this neurological
hereditary disorder is that the gestures and vocalizations of the affected
children, as young as eight or nine, may
be antisocial or obscene (though most are not).
They are compulsive, occurring
despite the patients' wish to withhold them.
There is much evidence that emotional tone, in particular, is generated more in the right hemisphere
than in the left. For example, aprosodia (loss of emotional tone of speech)
occurs after right hemisphere lesions,
not left. However, speech itself, except for singing overlearned songs and
swearing, is generated by the left hemisphere. For example,
a callosotomized patient (a patient who has had his or her corpus
callosum surgically severed) is totally unable to name things out loud if they
have been seen only in the part of the visual field that feeds the right
hemisphere. Could it be then, that patients with Gilles de la Tourette's
disease are subject to incoercible abnormal activation of the hemispheric
centers of spoken language in the left hemisphere (such as Broca's area of the
posterior dorsolateral frontal lobe), themselves
throttled by inordinate activation of right hemisphere-generated emotion, through a defective and unbridled anterior
corpus callosum ? There is not much
evidence apt to determine the fate of this idea. A recent study was the first to investigate
gross size of the corpus callosum in Gilles de la Tourette's disease, using radiological brain imaging. The corpus callosum had a significantly
abnormal morphology.
Unfortunately, nothing is known
at all about interhemispheric relay in this disorder.
Finally, the
most interesting and potentially important example of a disorder suggestive of
callosal dysfunction, is
stuttering. There are two to three
times more boy than girl stutterers. It
is well accepted that only the left hemisphere can produce deliberate
spontaneous speech (we exclude from this singing, swearing or the like). Suppose though, that during speech, an abnormal influence would come from the
motor areas (especially, I think, an
area called the supplementary motor cortex of the frontal lobe) of the other
hemisphere, unbridled ? This would easily explain why dysrythmia
of speech (stammering, stuttering, hesitations, etc.) would occur. A disruptive neural activation from the right
hemisphere would interfere with the activities of the left hemisphere during
speech. There is only indirect evidence
that this could be the case. When
stutterers are asked to do a different task with each hand, simultaneously, it has been repeatedly found that the part of
the brain controlling the left hand (the right hemisphere, probably specifically the supplementary motor
cortex) interferes with the part of the brain controlling the right hand (the
same area of the left hemisphere).
This is deduced from effects observed in right and left hand
performance, not from observations of
the brain itself. What remains to be
done at this point is a magnetic resonance imaging study of the corpus callosum
of stutterers and a control group, and
physiological studies of interhemispheric relay. Interestingly, some enterprising neurosurgeons have not
waited for these studies to start relieving their heavily affected patients by
means of callosotomy. The procedure
consists of beaming a high intensity focused magnetic energy force at the
corpus callosum. This beam is known to harmlessly inactivate the targeted
neurons. If the patient stops
stuttering, he becomes a reasonable
candidate for the surgery. Table 3
presents details of sex differences in callosal dysfunction.
Table 3
Pediatric neuropsychological syndromes
believed to comprise callosal dysfunction and for which the male child is at
greater risk and/or is more severely affected
Syndrome
|
Reference
|
Head trauma***
|
Brooks, 1985
|
Schizophrenia* **
|
Szymanski et al, 1995
|
Dyslexia* **
|
Geschwind et al, 1985
|
Tourette’s disease* **
|
Hyde et al, 1993
|
Fetal alcohol syndrome**
|
Zimmerberg, 1991
|
Stuttering* **
|
Andrews et al, 1964
|
Attention-deficit hyperactivity
disorder* **
|
Szatmari et al, 1989
|
Alexithymia* **
|
Saarijarvi, 1993
|
Prenatal malnutrition**
|
Galler, 1981
|
Learning disabilities * **
|
Schacter et al, 1987
|
Note.
A single asterisk indicates a congenital male-prevalent disorder, a double asterisk indicates a more severe
expression of the behavioral disorder,
and a triple asterisk indicates a non congenital disorder involving
callosal dysfunction for which the boy is more at risk than the girl.
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